The presynaptic protein alpha-synuclein has received much attention because its gain-of-function is associated with Parkinson’s disease. However, its physiological function is still poorly understood. We studied brain regions of knock-out mice at different ages with regard to consistent upregulations of the transcriptome and focused on glyoxalase I (GLO1). The microarray data were confirmed in qPCR, immunoblot, enzyme activity, and behavior analyses. GLO1 induction is a known protective cellular response to glucose stress, representing efforts to decrease toxic levels of methylglyoxal (MG), glyoxal and advanced glycation endproducts (AGEs). Mass spectrometry quantification demonstrated a ubiquitous increase in MG and fructosyl-lysine as consequences of glucose toxicity, and consistent enhancement of certain AGEs. Thus, GLO1 induction in KO brain seems insufficient to prevent AGE formation. In conclusion, the data demonstrate GLO1 expression and glycation damage to be induced by alpha-synuclein ablation. We propose that wild-type alpha-synuclein modulates brain glucose metabolism.